October 25, 2006

Case School of Medicine professor discovers nerve cell defects caused by mental retardation gene

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Neuroscientists at Case Western Reserve University School of Medicine have discovered changes in nerve cell function caused by mutation of the gene responsible for Rett Syndrome, a devastating progressive neurological disorder. As reported this week in the Journal of Neuroscience, a team led by David M. Katz, PhD, Professor of Neurosciences, has found changes in the way that nerve and endocrine cells regulate the secretion of molecules that are critical for cell-to-cell communication and the body's response to stress.

Rett Syndrome, one of the most common causes of retardation in females, is a severely debilitating disorder afflicting at least one in every 10,000 female births. The onset and progression of the syndrome is particularly tragic—a seemingly healthy female baby unexpectedly enters a period of developmental regression, between 6 and 18 months of age, during which her head growth decelerates, she begin to lose acquired speech and motor skills and develops stereotyped, repetitive movements. This initial period is often heralded by visible signs of distress, including inconsolable crying or screaming for weeks or months. Within a few years, most of these girls develop severe mental retardation, highly irregular breathing and heart rate control, seizures, feeding problems and lack of motor control. Families are devastated as they watch their child suffer through this reversion to an increasingly infantile-like state of dependency. Rett Syndrome leaves its victims profoundly disabled, requiring full-time assistance with every aspect of daily living. There is no cure.

"The gene responsible for Rett Syndrome, called Mecp2, was discovered in 1999 and, since that time, research into the disease has accelerated rapidly," Dr. Katz said. Within the last few years, mouse models of Rett Syndrome have become available that have made it possible to probe in depth how mutations of Mecp2 derange neurological development. At the same time, clinical research has revealed that mutations in this same gene are involved in other disorders, including some forms of autism. The study of disease mechanisms in Rett Syndrome has provided a window into fundamental processes of brain development.

With grants from the National Institutes of Health and the Rett Syndrome Research Foundation, Dr. Katz and his team have been able to zero in on problems in the way nerve cells regulate the production and secretion of one particular molecule, brain derived neurotrophic factor (BDNF), that is critically important for brain development and function. Basically, using nerve cells grown in culture, they found that there is a disruption in the normal balance between how much BDNF a cell makes and how much is secreted. This is likely to lead to situations in which nerve cells release either too much or too little BDNF, thus disrupting processes that depend on precise regulation of BDNF levels. Moreover, in collaboration with Corey Smith, PhD, Associate Professor of Physiology and Biophysics, and Shyu-en Chan, a postdoctoral associate in Smith's lab, Professor Katz's team has identified similar problems with the secretion of adrenal hormones called catecholamines. Dr. Katz believes that these secretion defects may therefore be a common thread contributing to the complex problems in the brain and other organ systems that characterize Rett Syndrome. The defects identified by Dr. Katz and his colleagues may be also be relevant to other brain disorders in which BDNF is implicated, including Huntington Disease, schizophrenia and depression. However, Katz cautions that his research is still in early stages.

Dr. Katz is keenly aware that to help children suffering from Rett Syndrome it will be necessary to translate basic research findings into potential therapies. "We know that chemical communication between nerve cells is abnormal but don't yet understand the underlying mechanisms in detail. In addition to working on elucidating disease mechanisms in Rett Syndrome, we are also actively pursuing experimental strategies for correcting the defects we have identified in the mouse model."

The other members of Katz's research team include postdoctoral research associates Hong Wang, PhD, Michael Ogier, PhD and Qifang Wang, MD, Tom Ladas, an MD, PhD student working in the Katz and Smith labs and Devraj Sukul, a Case Western Reserve University undergraduate.

Additional information on Rett Syndrome can be found at http://www.rsrf.org, the website of the Rett Syndrome Research Foundation.

About Case Western Reserve University School of Medicine

Founded in 1843, the Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and 12th largest among the nation's medical schools for research funding from the National Institutes of Health. Eleven Nobel Laureates have been affiliated with the school.

The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. In 2002, it became only the third medical school in history to receive the best review possible from the national body responsible for accrediting the nation's medical schools. It ranks in the top 25 among U.S. research-oriented medical schools in the U.S. News and World Report guide to graduate education. Annually, the School of Medicine trains more than 600 M.D. and M.D./Ph.D. students. The School's Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century.

The School of Medicine's primary clinical affiliate is University Hospitals at Case Medical Center and the school is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic Foundation, with which it opened the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2004. http://casemed.case.edu

Story by Susan Licate, 216.368.3635.

Posted by: Heidi Cool, October 25, 2006 12:01 PM | News Topics: HeadlinesMain, Provost Initiatives, Research, School of Medicine

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